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  • MECHANISM  (24)
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  • 1
    Keywords: ESTROGEN ; estrogen receptor ; in vivo ; THERAPIES ; ESTROGEN-RECEPTOR ; mechanisms ; DISSECTION ; LIGANDS ; RECEPTOR ; IN-VIVO ; THERAPY ; VIVO ; MECHANISM ; LIGAND
    Type of Publication: Book chapter
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  • 2
    Keywords: brain ; EXPRESSION ; MODEL ; MODELS ; SYSTEM ; COHORT ; GENE ; PROTEIN ; transcription ; DRUG ; MICE ; RESPONSES ; MECHANISM ; TRANSCRIPTION FACTOR ; RATS ; mechanisms ; BINDING ; ALPHA ; CREB ; ELEMENT ; ELEMENT-BINDING PROTEIN ; ISOFORM ; MUTANT ; NERVOUS-SYSTEM ; NO ; TARGETED MUTATION ; DECREASE ; STRESS ; MUTATION ; MODULATION ; REGION ; REGIONS ; Jun ; INVOLVEMENT ; BEHAVIOR ; FOOD ; LACKING ; BINDING PROTEIN ; molecular ; BINDING-PROTEIN ; MOLECULAR-MECHANISM ; DEPENDENCE ; NEURONS ; KNOCKOUT MICE ; ADDICTION ; CERULEUS ; conditioned place preference ; emotional behavior ; locus coeruleus ; LOCUS-COERULEUS NEURONS ; MOLECULAR-MECHANISMS ; NEURAL PLASTICITY ; opiate addiction ; OPIATE-WITHDRAWAL
    Abstract: The transcription factor cAMP-responsive element binding protein (CREB) has been shown to regulate different physiological responses including drug addiction and emotional behavior. Molecular changes including adaptive modifications of the transcription factor CREB are produced during drug dependence in many regions of the brain, including the locus coeruleus (LC), but the molecular mechanisms involving CREB within these regions have remained controversial. To further investigate the involvement of CREB in emotional behavior, drug reward and opioid physical dependence, we used two independently generated CREB-deficient mice. We employed the Cre/loxP system to generate mice with a conditional CREB mutation restricted to the nervous system, where all CREB isoforms are lacking in the brain (Creb / (NesCre)). A genetically defined cohort of the previously described hypomorphic Creb / (alphaDelta) mice, in which the two major transcriptionally active isoforms (alpha and Delta) are disrupted throughout the organism, were also used. First, we investigated the responses to stress of the CREB-deficient mice in several paradigms, and we found an increased anxiogenic-like response in the both Creb / mutant mice in different behavioral models. We investigated the rewarding properties of drugs of abuse (cocaine and morphine) and natural reward (food) using the conditioned place-preference paradigm. No modification of motivational responses of morphine, cocaine, or food was observed in mutant mice. Finally, we evaluated opioid dependence by measuring the behavioral expression of morphine withdrawal and electrophysiological recordings of LC neurons. We showed an important attenuation of the behavioral expression of abstinence and a decrease in the hyperactivity of LC neurons in both Creb / mutant mice. Our results emphasize the selective role played by neuronal CREB in emotional-like behavior and the somatic expression morphine withdrawal, without participating in the rewarding properties induced by morphine and cocaine
    Type of Publication: Journal article published
    PubMed ID: 15029152
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  • 3
    Keywords: brain ; RECEPTOR ; CELLS ; PATHWAY ; PATHWAYS ; GENE ; GENES ; RELEASE ; RESPONSES ; MECHANISM ; FREQUENCY ; hormone ; STRESS ; inactivation ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; glucocorticoid receptor ; LIVING CELLS ; RECEPTORS ; GLUCOCORTICOID-RECEPTOR ; ANTAGONIST ; rodent ; SUBCELLULAR-LOCALIZATION ; signaling ; NEURONS ; LIFE ; ENHANCEMENT ; ESTROGEN ; corticosteroid ; mineralocorticoid receptor ; LEVEL ; function ; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor CA1 hippocampus ; glucocorticoid receptor knockout ; MICRODIALYSIS ; mineralocorticoid receptor knockout ; miniature excitatory postsynaptic current ; RAT HIPPOCAMPUS ; SYNAPSES
    Abstract: The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways
    Type of Publication: Journal article published
    PubMed ID: 16361444
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  • 4
    Keywords: brain ; RECEPTOR ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VIVO ; SYSTEM ; TOOL ; METABOLISM ; MICE ; ACTIVATION ; RESPONSES ; MECHANISM ; mechanisms ; hippocampus ; MOUSE ; NERVOUS-SYSTEM ; DISRUPTION ; STRESS ; MUTATION ; DNA-BINDING ; MUTATIONS ; MOUSE MODEL ; glucocorticoid receptor ; DOMAINS ; DISSECTION ; review ; RE ; RESPONSIVENESS ; FOREBRAIN ; TECHNOLOGY ; LOSSES ; ENGLAND ; steroids ; STEROID-HORMONE RECEPTORS ; CRE RECOMBINASE ACTIVITY ; cortisol/corticosterone ; HPA axis
    Abstract: In the brain, glucocorticoids exert functions in neurogenesis, synaptic plasticity and behavioural responses, as well as in the control of hypothalamic-pituitary-adrenal axis activity. The generation of mice harbouring germline mutations that result either in loss or in gain of glucocorticoid receptor function provided a useful tool for understanding the role of glucocorticoids in the brain in vivo. The improvement of genomic technologies additionally allowed the establishment of mouse models with function-selective point mutations of the receptor as well as the generation of mice harbouring spatially and/or temporally restricted loss of glucocorticoid receptor, specifically within the brain. These models will provide the opportunity to better understand the mechanisms involved in glucocorticoid signalling within the nervous system
    Type of Publication: Journal article published
    PubMed ID: 18513206
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  • 5
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; CELL ; MODEL ; MODELS ; GENE ; transcription ; METABOLISM ; DIFFERENTIATION ; MICE ; ACTIVATION ; DNA ; MECHANISM ; MARKER ; primary ; INDUCTION ; KERATINOCYTES ; mechanisms ; SKIN ; MATURATION ; MOUSE ; NUMBER ; DNA-BINDING ; SIGNALING PATHWAY ; epidermis ; ARCHITECTURE ; desmosomes ; USA ; LOSSES ; HOMEOSTASIS ; BARRIER ; CASPASE-14 ; EPIDERMAL-KERATINOCYTES ; FETAL MOUSE
    Abstract: To investigate the contribution of the glucocorticoid receptor (GR) in skin development and the mechanisms underlying this function, we have analyzed two mouse models in which GR has been functionally inactivated: the knockout GR(-/-) mice and the dimerization mutant GR(dim/dim) that mediates defective DNA binding-dependent transcription. Because GR null mice die perinatally, we evaluated skin architecture of late embryos by histological, immunohistochemical, and electron microscopy studies. Loss of function of GR resulted in incomplete epidermal stratification with dramatically abnormal differentiation of GR(-/-), but not GR(+/-) embryos, as demonstrated by the lack of loricrin, filaggrin, and involucrin markers. Skin sections of GR(-/-) embryos revealed edematous basal and lower spinous cells, and electron micrographs showed increased intercellular spaces between keratinocytes and reduced number of desmosomes. The absent terminal differentiation in GR(-/-) embryos correlated with an impaired activation of caspase-14, which is required for the processing of profilaggrin into filaggrin at late embryo stages. Accordingly, the skin barrier competence was severely compromised in GR(-/-) embryos. Cultured mouse primary keratinocytes from GR(-/-) mice formed colonies with cells of heterogeneous size and morphology that showed increased growth and apoptosis, indicating that GR regulates these processes in a cell-autonomous manner. The activity of ERK1/2 was constitutively augmented in GR(-/-) skin and mouse primary keratinocytes relative to wild type, which suggests that GR modulates skin homeostasis, at least partially, by antagonizing ERK function. Moreover, the epidermis of GR(+/dim) and GR(dim/dim) embryos appeared normal, thus suggesting that DNA-binding-independent actions of GR are sufficient to mediate epidermal and hair follicle development during embryogenesis
    Type of Publication: Journal article published
    PubMed ID: 18039792
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  • 6
    Keywords: RECEPTOR ; APOPTOSIS ; CANCER ; CELLS ; GROWTH ; IN-VITRO ; tumor ; carcinoma ; CELL ; human ; IN-VIVO ; MODEL ; MODELS ; PATHWAY ; VITRO ; SYSTEM ; incidence ; GENE ; MICE ; PATIENT ; MECHANISM ; primary ; SKIN ; SUPPRESSION ; PROGRESSION ; NUMBER ; MELANOMA ; CANCER-CELLS ; RECEPTORS ; CHILDHOOD NEUROBLASTOMAS ; APOPTOSIS-INDUCING LIGAND ; AGENT ; CELL CARCINOMA ; RE ; TUMOR-GROWTH ; INCREASE ; CASPASE-8 ; C-FLIP ; SUPPRESSOR ; death receptor ; USA ; MEDICINE ; anoikis
    Abstract: TRAIL is a promising anticancer agent due to its ability to selectively induce apoptosis in established tumor cell lines but not nontransformed cells. Herein, we demonstrate a role for the apoptosis-inducing TRAIL receptor (TRAIL-R) as a metastasis suppressor. Although mouse models employing tumor transplantation have shown that TRAIL can reduce tumor growth, autochthonous tumor models have generated conflicting results with respect to the physiological role of the TRAIL system during tumorigenesis. We used a multistage model of squamous cell carcinoma to examine the role of TRAIL-R throughout all steps of tumor development. DMBA/TPA-treated TRAIL-R-deficient mice showed neither an increase in number or growth rate of benign papillomas nor an increase in the rate of progression to squamous cell carcinoma. However, metastasis to lymph nodes was significantly enhanced, indicating a role for TRAIL-R specifically in the suppression of metastasis. We also found that adherent TRAIL-R-expressing skin carcinoma cells were TRAIL resistant in vitro but were sensitized to TRAIL upon detachment by inactivation of the ERK signaling pathway. As detachment from the primary tumor is an obligatory step in metastasis, this provides a possible mechanism by which TRAIL-R could inhibit metastasis. Hence, treatment of cancer patients with agonists of the apoptosis-inducing receptors for TRAIL may prove useful in reducing the incidence of metastasis
    Type of Publication: Journal article published
    PubMed ID: 18079967
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  • 7
    Keywords: RECEPTOR ; EXPRESSION ; IN-VITRO ; PROTECTION ; Germany ; IN-VIVO ; VITRO ; VIVO ; SYSTEM ; SYSTEMS ; NEW-YORK ; MICE ; MECHANISM ; mechanisms ; TYPE-1 ; ACID ; NERVOUS-SYSTEM ; DAMAGE ; CENTRAL-NERVOUS-SYSTEM ; MUTANT MICE ; max ; ACUTE NEURONAL INJURY ; ANANDAMIDE ; ENDOCANNABINOIDS ; GLUTAMATE ; N-ACYLETHANOLAMINE PHOSPHOLIPIDS ; NEUROPROTECTION ; RAT-BRAIN ; SEIZURE
    Abstract: Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice, the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons
    Type of Publication: Journal article published
    PubMed ID: 14526074
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  • 8
    Keywords: RECEPTOR ; CELL ; Germany ; PATHWAY ; MICE ; MECHANISM ; mechanisms ; ALPHA ; virus ; MOUSE ; NERVOUS-SYSTEM ; hormone ; LINE ; REGION ; REGIONS ; BETA ; MUTANT MICE ; RAT-BRAIN ; ESTROGEN-RECEPTOR ; RE ; DEPENDENT PROTEIN-KINASE ; ESTROGEN ; estrogen receptor ; PSEUDORABIES VIRUS ; neuron ; FEMALE RAT ; LHRH NEURONS ; LUTEINIZING-HORMONE ; PREOPTIC AREA ; SURGE
    Abstract: The mechanisms through which estrogen regulates gonadotropin-releasing hormone (GnRH) neurons to control mammalian ovulation are unknown. We found that estrogen positive feedback to generate the preovulatory gonadotropin surge was normal in estrogen receptor beta knockout (ER beta) mutant mice, but absent in ER alpha mutant mice. An ER alpha-selective compound was sufficient to generate positive feedback in wild-type mice. As GnRH neurons do not express ER alpha, estrogen positive feedback upon GnRH neurons must be indirect in nature. To establish the cell type responsible, we generated a neuron-specific ERa mutant mouse line. These mice failed to exhibit estrogen positive feedback, demonstrating that neurons expressing ER alpha are critical. We then used a GnRH neuron-specific Pseudorabies virus (PRV) tracing approach to show that the ER alpha-expressing neurons innervating GnRH neurons are located within rostral periventricular regions of the hypothalamus. These studies demonstrate that ovulation is driven by estrogen actions upon ER alpha-expressing neuronal afferents to GnRH neurons
    Type of Publication: Journal article published
    PubMed ID: 17046690
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  • 9
    Keywords: RECEPTOR ; CELLS ; CELL ; Germany ; GENE ; PROTEIN ; PROTEINS ; TISSUE ; MICE ; TUMOR-NECROSIS-FACTOR ; DNA ; MACROPHAGES ; MECHANISM ; CONTRAST ; DENDRITIC CELLS ; KERATINOCYTES ; mechanisms ; SKIN ; T cell ; T cells ; T-CELL ; T-CELLS ; SUPPRESSION ; treatment ; cytokines ; TARGET ; MUTANT ; inactivation ; DNA-BINDING ; BETA ; MOUSE MODEL ; TARGETS ; side effects ; REPRESSION ; DIMERIZATION ; chemokine ; TNF-ALPHA ; NEUTROPHILS ; CYTOKINE ; molecular ; PERSISTENT ; RECOMBINANT ; INFILTRATION ; MOLECULAR-MECHANISM ; RE ; keratinocyte ; allergy ; IMMUNE SUPPRESSION ; chemokines ; INFLAMMATORY CYTOKINES ; MOLECULAR-MECHANISMS ; PHASE ; USA ; corticosteroids ; GLUCOCORTICOIDS ; RESISTANT ; SKIN INFLAMMATION ; CONTACT ; MEDICINE ; INFLAMMATORY RESPONSE ; EPIDERMAL LANGERHANS CELLS ; HYPERSENSITIVITY REACTIONS ; INFLAMMATORY PROTEIN-2
    Abstract: Glucocorticoids (GCs) are widely used in the treatment of allergic skin conditions despite having numerous side effects. Here we use Cre/loxP-engineered tissue- and cell-specific and function-selective GC receptor (GR) mutant mice to identify responsive cell types and molecular mechanisms underlying the and inflammatory activity of GCs in contact hypersensitivity (CHS). CHS was repressed by GCs only at the challenge phase, i.e., during reexposure to the hapten. Inactivation of the GR gene in keratinocytes or T cells of mutant mice did not attenuate the effects of GCs, but its ablation in macrophages and neutrophils abolished downregulation of the inflammatory response. Moreover, mice expressing a DNA binding-defective GR were also resistant to GC treatment. The persistent infiltration of macrophages and neutrophils in these mice is explained by an impaired repression of inflammatory cytokines and chemokines such as IL-1 beta, monocyte chemoattractant protein-1, macrophage inflammatory protein-2, and IFN-gamma-inducible protein 10. In contrast TNF-alpha repression remained intact. Consequently, injection of recombinant proteins of these cytokines and chemokines partially reversed suppression of CHS by GCs. These studies provide evidence that in contact allergy, therapeutic action of corticosteroids is in macrophages and neutrophils and that dimerization GR is required
    Type of Publication: Journal article published
    PubMed ID: 17446934
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  • 10
    Keywords: RECEPTOR ; EXPRESSION ; proliferation ; Germany ; IN-VIVO ; MODEL ; VIVO ; SUPPORT ; liver ; GENE ; GENE-EXPRESSION ; microarray ; transcription ; DRUG ; METABOLISM ; MICE ; ACTIVATION ; LIGAND ; DNA ; MECHANISM ; DOMAIN ; mechanisms ; BINDING ; DISCOVERY ; RECOGNITION ; ACID ; TARGET ; MOUSE ; gene expression ; MICROARRAY DATA ; DISRUPTION ; WOMEN ; DNA-BINDING ; EXCHANGE ; LIGANDS ; PHENOTYPE ; MOUSE MODEL ; GLUCOCORTICOID-RECEPTOR ; REPRESSION ; expression profiling ; ER ; ESTROGEN-RECEPTOR ; TRANSCRIPTIONAL REGULATION ; MAMMARY-GLAND ; regulation ; AMINO-ACID ; DRUG DISCOVERY ; MOUSE-LIVER ; development ; ESTROGEN ; LOCUS ; estrogen receptor ; USA ; DNA binding ; AGREEMENT ; BREAST-CANCER CELLS ; ESTROGENS ; POSITION ; RECEPTOR-ALPHA ; Genetic ; ALPHA GENE ; ER-ALPHA ; HORMONE-THERAPY ; MUTATION PROVIDES EVIDENCE
    Abstract: The majority of the biological effects of estrogens in the reproductive tract are mediated by estrogen receptor (ER)alpha, which regulates transcription by several mechanisms. Because the tissue-specific effects of some ER alpha ligands may be caused by tissue-specific transcriptional mechanisms of ER alpha, we aimed to identify the contribution of DNA recognition to these mechanisms in two clinically important target organs, namely uterus and liver. We used a genetic mouse model that dissects DNA binding-dependent vs. independent transcriptional regulation elicited by ER alpha. The EAAE mutant harbors amino acid exchanges at four positions of the DNA-binding domain (DBD) of ER alpha. This construct was knocked in the ER alpha gene locus to produce ER alpha((EAAE/ EAAE)) mice devoid of a functional ER alpha DBD. The phenotype of the ER alpha((EAAE/EAAE)) mice resembles the general loss-of-function phenotype of alpha ER knockout mutant mice with hypoplastic uteri, hemorrhagic ovaries, and impaired mammary gland development. In agreement with this phenotype, the expression pattern of the ER alpha((EAAE/EAAE)) mutant mice in liver obtained by genome-wide gene expression profiling supports the observation of a near-complete loss of estrogen-dependent gene regulation in comparison with the wild type. Further gene expression analyses to validate the results of the microarray data were performed by quantitative RT-PCR. The analyses indicate that both gene activation and repression by estrogen-bound ER alpha rely on an intact DBD in vivo. (Molecular Endocrinology 23: 1544-1555, 2009)
    Type of Publication: Journal article published
    PubMed ID: 19574448
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